5HT-4 agonists and opioid receptor antagonists are synergistic in enhancing velocity of propulsion of pellets and facilitating colonic emptying in vitro studies. The therapeutic effect of the combination of therapies in human subjects is unknown. Our hypothesis is that 5-HT4 agonists and opioid antagonists are synergistic in enhancing colonic propulsion in humans. Thus, we aim to compare dose response effects of tegaserod and methylnaltrexone alone and in combination on intestinal transit in healthy subjects and to determine the coefficient of variation of response to individual or combined therapies to facilitate planning of phase II clinical trials in patients with delayed transit motility disorders. This is a randomized, multiple dose, parallel group, double-dummy blinded, placebo-controlled study evaluating the dose response and pharmacodynamic effects of tegaserod 2 or 6 mg plus placebo, methylnaltrexone 500 or 1500 mg plus placebo, and tegaserod 2 or 6 mg plus methylnaltrexone 500 or 1500 mg vs placebo on gastrointestinal and colon transit in healthy volunteers. The endpoints, which have been validated in the laboratory include gastric and small intestine transit, ascending colon transit t1/2and total colonic transit. The sample size of 10 patients per group provides 80% power to detect a synergistic drug interaction using a two-sample z-test at a two-sided alpha level of 0.05 for the primary endpoint. We anticipate that a combination of tegaserod and methylnaltrexone is synergistic and will enhance colonic propulsion by 40% over either drug individually in healthy human subjects. This study will form the foundation for subsequent applications for Federal funding evaluating the role of these treatments to modulate intestinal peristalsis and improve motility. Thus, this work should lead to novel approaches to therapies for patients with motility disorders, such as gastroparesis, slow transit constipation and pseudoobstruction for which current therapy is suboptimal.